WO2022105838A1 - 氨基酸聚合物或多肽模拟聚合物在骨修复中的应用 - Google Patents

氨基酸聚合物或多肽模拟聚合物在骨修复中的应用 Download PDF

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WO2022105838A1
WO2022105838A1 PCT/CN2021/131541 CN2021131541W WO2022105838A1 WO 2022105838 A1 WO2022105838 A1 WO 2022105838A1 CN 2021131541 W CN2021131541 W CN 2021131541W WO 2022105838 A1 WO2022105838 A1 WO 2022105838A1
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amino acid
polymer
alkyl
substituted
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刘润辉
陈琦
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华东理工大学
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/42—Polyamides containing atoms other than carbon, hydrogen, oxygen, and nitrogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/42—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having an inorganic matrix
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/02—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids
    • C08G69/08—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids derived from amino-carboxylic acids
    • C08G69/14—Lactams
    • C08G69/16—Preparatory processes
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J7/00—Chemical treatment or coating of shaped articles made of macromolecular substances
    • C08J7/04—Coating
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J7/00—Chemical treatment or coating of shaped articles made of macromolecular substances
    • C08J7/12—Chemical modification
    • C08J7/16—Chemical modification with polymerisable compounds
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L87/00—Compositions of unspecified macromolecular compounds, obtained otherwise than by polymerisation reactions only involving unsaturated carbon-to-carbon bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

Definitions

  • the invention relates to the field of bone repair materials, in particular to the application of amino acid polymers and polypeptide-simulating polymers in bone repair.
  • the early bone repair materials were mainly natural biomaterials, which were derived from living organisms and had good biocompatibility.
  • many shortcomings such as immunogenicity, possible pathogenic bacteria, and unstable components between batches limited their application.
  • artificial materials With the development of science and technology, artificial materials continue to emerge, which can overcome many shortcomings of natural materials, but poor biological activity is the bottleneck restricting their development.
  • the primary premise of bioactive materials is to support cell adhesion, so as to realize a series of physiological activities such as cell proliferation, migration, and differentiation.
  • it is usually necessary to modify a layer of active molecules on the surface of inert materials to promote cell adhesion and thus improve histocompatibility.
  • cells mainly combine some receptors on the membrane with extracellular matrix proteins (ECM proteins) to achieve cell adhesion, in which there are some specific sequences of active polypeptides (eg: RGD, KRSR) in the ECM proteins.
  • ECM proteins extracellular matrix proteins
  • Modifying the protein/polypeptide with cell adhesion function on the surface of the implant material can improve the cell adhesion effect of the material, but the natural protein/polypeptide is easily degraded in the body, and bone tissue repair is a long process and expensive. , the difficulty in mass production greatly limits its clinical application.
  • the purpose of the present invention is to have good cell adhesion and bone repair functions, and at the same time, the material is simple to prepare, cheap, and has good in vivo stability and even can be degraded.
  • the present invention provides the application of an amino acid polymer, a polypeptide-mimicking polymer or a pharmaceutically acceptable salt thereof, for modifying the surface of a bone implant material or doping the inside thereof; or for preparing a bone repair material.
  • the amino acid polymer has the same meaning as the polypeptide polymer.
  • a polypeptide polymer mimetic has the same meaning as a polypeptide mimetic polymer.
  • bone repair includes bone filling and bone replacement.
  • the amino acid polymer or polypeptide mimicking polymer or a pharmaceutically acceptable salt thereof is used as an active molecule related to bone repair, and is doped inside the bone implant material or carried out on the surface of the bone implant material. Modification for promoting the osseointegration effect of bone implant materials.
  • the amino acid polymer or polypeptide-mimicking polymer or a pharmaceutically acceptable salt thereof is used to prepare a scaffold material for bone repair.
  • the amino acid polymer or polypeptide-mimicking polymer of the present invention or a pharmaceutically acceptable salt thereof can promote the cell adhesion, proliferation, migration, differentiation and other functions of bone repair-related cells during the above application process, thereby promoting osteogenic repair effect and osseointegration effect.
  • the cells related to bone repair are one or a combination of two or more of osteoblasts, pre-osteoblasts, stem cells, and macrophages.
  • the bone implant material includes bone filling material and bone replacement material.
  • the bone implant material is a non-degradable permanent implant material or a degradable implant material.
  • the non-degradable permanent implant material is selected from: titanium, porous titanium, titanium alloy, titanium-nickel alloy, tantalum metal, magnesium metal, magnesium alloy, stainless steel, cobalt-chromium alloy, polymethacrylic acid Methyl ester, polyurethane, polyether ether ketone, polyacrylamide, polyvinyl alcohol.
  • the degradable implant material is selected from the group consisting of: polylactic acid, poly(lactic acid-glycolic acid) copolymer, polylactide, polyglycolide, polyglycolide, polycaprolactone , Polycaprolactone, Alumina, Zirconia, Hydroxyapatite, Tricalcium Phosphate, Bioglass, Collagen, Hyaluronic Acid, Chitosan, Alginate, Silk Fibroin, Fibrin, Gelatin, Cellulose .
  • the bone implant material is an inert implant material.
  • the bone repair material is in the form of hydrogel, electrospun membrane, 3D printed scaffold, porous scaffold, solid scaffold, bone cement, injectable bone material, in vivo cross-linked bone material, composite material one or a combination of two or more.
  • the amino acid polymer or polypeptide mimicking polymer is one or more homopolymers, binary copolymers or multicomponent copolymers selected from the following group: ⁇ -amino acid, ⁇ -amino acid , ⁇ -amino acid, oxazoline.
  • the amino acid polymer or polypeptide mimic polymer is an oxazoline polymer, ⁇ -amino acid polymer, ⁇ / ⁇ -amino acid polymer, ⁇ -amino acid polymer or ⁇ -amino acid polymer.
  • amino acid polymer or polypeptide mimic polymer is the following Aa, Aa', Bb, Bb', Cc, Cc', Cc", Dd, Dd', Ee, Ee', Ff, Ff ' and Gg structures composed of homopolymers, binary copolymers or multi-component copolymers, the total number of repeating units is a positive integer of 5-5000:
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 in the formula, where present, are each independently selected from the following groups: hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 Alkylhydroxy, C1-C6 alkoxy, C1-C6 alkylsulfonyl, C1-C6 alkylguanidino, C1-C6 alkyl ester, thioC1-C6 alkyl ester, C2-C6 alkenyl , C2-C6 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 5-12-membered heteroaryl, 5-12-membered heterocyclyl, C1-C6 alkyl-C6-C12 aryl, amino and
  • P1 is a protecting group independently selected at each occurrence from the following groups: tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), phthaloyl (Pht), Acetyl (Ac), trifluoroacetyl (Tfa), benzyl (Bn), triphenylmethyl (Tr);
  • P2 at each occurrence is independently selected from the following groups: hydrogen , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted 5-12 membered heteroaryl , substituted or unsubstituted 5-12-membered heterocyclyl;
  • X at each occurrence is independently selected from the following groups: none, hydrogen, amino, guanidino, hydroxy, carboxyl, amido, mercapto, methylthio, alkenyl, alkynyl, ester, aryl, or 5-12 membered heterocyclic group;
  • R'1 at each occurrence is independently selected from the following groups, substituted or unsubstituted: hydrogen, amino, C1-C15 alkyl, C1-C15 alkylamino, C1-C15 alkylhydroxy, C1-C15 alkylaldehyde group, C1-C15 alkyl ester group, thio-C1-C15 alkyl ester group, C6-C15 aryl group, C2-C15 alkenyl group, C2-C15 alkynyl group, -Rc-COO-Rc", -Rc-CO -Rc", -Rc-O-Rc"-, -Rc-S-Rc", 5-15-membered heteroaryl, 5-12-membered heterocyclyl;
  • R a and R b at each occurrence are each independently selected from the following groups, substituted or unsubstituted: absent, hydrogen, C1-C15 alkyl, C1-C15 alkylamino, C1-C15 alkylhydroxy, C1- C15 alkyl aldehyde group, C1-C15 alkyl sulfonyl group, C2-C15 alkenyl group, C2-C15 alkynyl group, -Rc-COO-Rc", -Rc-CO-Rc", -Rc-O-Rc"- , -Rc-S-Rc", C3-C12 cycloalkyl, C4-C12 cycloalkenyl, 5-12-membered heterocyclyl, C6-C12 aryl, 5-12-membered heteroaryl;
  • Rc is each independently selected from the group consisting of substituted or unsubstituted: none, C1-C15 alkylene, C2-C15 alkenylene, C2-C15 alkynylene, C3-C12 cycloalkylene, C4-C12 cycloalkenylene, 3-12-membered heterocyclylene, C6-C12 arylene, 5-12-membered heteroarylene;
  • Rc is each independently selected from the following groups, substituted or unsubstituted: C1-C15 alkyl, C1-C15 alkylamino, C2-C15 alkenyl, C2-C15 alkynyl, C3-C12 cycloalkane base, C4-C12 cycloalkenyl, 3-12 membered heterocyclyl, C6-C12 aryl, 5-12 membered heteroaryl,
  • Each of the above substitutions independently refers to being substituted by one or more substituents selected from the group consisting of halogen, hydroxy, amino, phenyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkane Oxygen, C3-C8 cycloalkyl.
  • the total number of repeating units is 5-100, preferably 5-50.
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently selected from the following groups where they appear: hydrogen, C1-C4 alkyl, C1-C4 haloalkyl , C1-C4 alkyl hydroxyl, C1-C4 alkoxy, C1-C4 alkyl sulfonyl, C1-C4 alkyl guanidino, C1-C4 alkyl ester, thio C1-C4 alkyl ester, C2 -C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, phenyl, naphthyl, 5-6 membered heteroaryl, 5-6 membered heterocyclyl, C1-C4 alkyl-C6 aryl, amino and
  • X is independently selected from the following groups at occurrence: none, hydrogen, amino, guanidino, hydroxyl, carboxyl, amido, mercapto, methylthio, alkenyl, alkynyl, ester ( -COO-), phenyl or 5-6 membered heterocyclyl.
  • L is independently selected from the group consisting of: -CH 2 -, -CO-, -COO- where it appears.
  • q is 0, 1, 2, 3, 4 or 5.
  • (L)q does not exist.
  • Ra and Rb are each independently selected from the group consisting of substituted or unsubstituted groups where they occur: absence, hydrogen, C1-C6 alkyl, C1-C6 alkylamino, C1-C6 alkane hydroxyl, C1-C6 alkyl aldehyde, C1-C6 alkylsulfonyl, C2-C6 alkenyl, C2-C6 alkynyl, -Rc-COO-Rc", -Rc-CO-Rc", -Rc- O-Rc"-, -Rc-S-Rc", C3-C6 cycloalkyl, C4-C6 cycloalkenyl, 5-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl.
  • the pharmaceutically acceptable salt is the hydrochloride, bromate, trifluoroacetate, phosphate, lithium, sodium, or potassium salt.
  • the structures of A, A', B, B', C, C', D, D', E, E', F, F' and G show that the amino acids are L-configuration, D-configuration form, or a mixture of both the D and L configurations.
  • the copolymer is a random copolymer, an alternating copolymer or a block copolymer. Preferably, it is a random copolymer.
  • the amino acid polymer or polypeptide mimetic polymer of the present invention also includes amino acid polymer or polypeptide mimetic polymer derivatives, and the derivative means that the amino group of the side chain of the polymer is changed to other functional groups such as guanidine group, etc., or the amino group contained in the side chain Connect other molecules through chemical reactions, such as drug molecules, fluorescent small molecules, protective groups, etc.; the end of the polymer is chemically modified, such as connecting fluorescent molecules or drug molecules.
  • amino acid polymer or polypeptide mimic polymer is selected from:
  • R z is selected from: halogen, carboxyl group, active ester group, acid chloride, alkylene oxide, mercapto group, C2-C15 alkene group, C2-C15 alkynyl group, azide, maleimide, o-dithiopyridyl ( OPSS), cyclodextrin, adamantane;
  • Rs are each independently hydrogen or R at each occurrence is independently selected from the following groups: C1-C15 alkyl, C1-C15 alkylamino, C2-C15 alkenyl, C2-C15 alkynyl, C3-C12 cycloalkyl, C4-C12 Cycloalkenyl, 3-12-membered heterocyclyl, C6-C12 aryl, 5-12-membered heteroaryl;
  • Rw is A wavy line indicates a connection;
  • A' is a positive integer from 0 to 12;
  • R 11 , R 12 , R 13 and R 14 in the formula are each independently selected from the following groups where they appear: hydrogen, C1-C6 alkyl , C1-C6 haloalkyl, C1-C6 alkyl hydroxyl, C1-C6 alkoxy, C1-C6 alkyl sulfonyl, C1-C6 alkyl guanidino, C1-C6 alkyl ester, thio C1-C6 Alkyl ester, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, C6-C12 aryl, 5-12-membered heteroaryl, 5-12-membered heterocyclyl, C1-C6 alkane base-C6-C12 aryl, amino and
  • P1 is a protecting group independently selected at each occurrence from the following groups: tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), phthaloyl (Pht), Acetyl (Ac), trifluoroacetyl (Tfa), benzyl (Bn), triphenylmethyl (Tr);
  • P2 at each occurrence is independently selected from the following groups: hydrogen , substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted 5-12 membered heteroaryl , substituted or unsubstituted 5-12-membered heterocyclyl;
  • Each of the above substitutions independently refers to being substituted by one or more substituents selected from the group consisting of halogen, hydroxy, amino, phenyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkane Oxygen, C3-C8 cycloalkyl.
  • the amino acid in the above structural unit is L-configuration, D-configuration, or a mixture of D-configuration and L-configuration.
  • the above-mentioned structural anions are selected from: Cl - , Br - , CF 3 COO - , H 2 PO 4 - , HPO 4 2- , PO 4 3- .
  • x and y are the ratios of each component, respectively, and the calculation method of x and y is that the number of repeating units of the corresponding component is divided by the total number of repeating units of the amino acid polymer or polypeptide-mimicking polymer.
  • amino acid polymer or polypeptide mimic polymer is selected from:
  • R z is selected from: halogen, carboxyl group, active ester group, acid chloride, alkylene oxide, mercapto (-SH), C2-C15 alkene group, C2-C15 alkynyl group, azide, maleimide, o-di Any of thiopyridyl (OPSS), cyclodextrin and adamantane.
  • the amino acid in the above structural unit is L-configuration, D-configuration, or a mixture of D-configuration and L-configuration.
  • the above-mentioned structural anions are selected from: Cl - , Br - , CF 3 COO - , H 2 PO 4 - , HPO 4 2- , PO 4 3- .
  • the arrangement form of the two repeating units in the above polymer structure is random, alternating or block, preferably, random.
  • n is 5-100, preferably 5-50.
  • x:y is 0.01:0.99 to 0.99:0.01, preferably 0.05:0.95 to 0.95:0.05, even 1:9 to 9:1.
  • the present invention provides a material or material composition that is easy to synthesize on a large scale, is inexpensive, has high in vivo stability or can be adjusted in stability, and supports bone repair-related cell adhesion, bone repair, and osseointegration;
  • the materials or material compositions (amino acid polymers and polypeptide-mimicking polymers) that support active functions such as cell adhesion provided by the present invention can obtain functions such as cell adhesion of bone repair-related cells without a specific amino acid sequence, and can Comparable to the cell adhesion gold standard RGD peptide.
  • the material or material composition (amino acid polymer and polypeptide mimicking polymer) that supports cell adhesion provided by the present invention can significantly improve the cell adhesion and other functions of the inert material, promote the compatibility of the material with bone tissue, and achieve Better osseointegration and bone repair effect, with huge clinical application advantages and value;
  • Example 1 Lithium hexamethyldisilazide (LiHMDS) initiation of DL-norleucine-N-carboxy intracyclic anhydride and N- ⁇ -tert-butoxycarbonyl-DL-lysine-N-carboxyl Random open condition copolymerization of intracyclic acid anhydrides
  • LiHMDS Lithium hexamethyldisilazide
  • Lithium hexamethyldisilazide (33.4 mg, 0.2 mmol) was accurately weighed, and prepared into a 0.1 M solution with tetrahydrofuran (2 mL) for use.
  • DL-norleucine-N-carboxy intracyclic acid anhydride (7.9 mg, 0.05 mmol) and N- ⁇ -tert-butoxycarbonyl-DL-lysine-N-carboxy intracyclic acid anhydride (20.4 mg, 0.075 mmol) (Monomer ratio 6:4)
  • Example 2 2-(Tritylthio)acetic acid-N-succinimidyl ester and lithium hexamethyldisilazide co-initiated ⁇ -lactam monomer NM and ⁇ -lactam monomer Preparation of random ⁇ -amino acid copolymers by CP
  • NM and CP In a nitrogen-protected glove box, weigh NM and CP, use dry THF (tetrahydrofuran) as a solvent, add a magnetron to the reaction flask, and take 1.2 mL of NM (0.2 M) and 0.8 mL of CP (0.2 M) for stirring. Then, p-2-(tritylthio)acetic acid-N-succinimidyl ester (0.2M) and lithium hexamethyldisilazide (0.5M) were prepared as co-initiators, each taking 100uL Add quickly to the reaction vial. The reaction was carried out at room temperature for 4 hours, and the reaction flask was taken out from the glove box and quenched by adding 1 drop of methanol.
  • THF tetrahydrofuran
  • Petroleum ether (45 mL) was added to the reaction solution, and after the white flocculent precipitate was precipitated, it was collected by centrifugation, dissolved in THF (1 mL), and precipitated with petroleum ether. After repeating this three times, a protected polymer was obtained. Then, trifluoroacetic acid (2 mL) was added to the protected polymer, and the protective group was removed by shaking for 2 hours. After blowing off most of the trifluoroacetic acid, ice methyl tert-butyl ether (50 mL) was added to precipitate a white precipitate and centrifuged. Collected, dissolved in methanol (1 mL), and precipitated with glacial ether (50 mL).
  • Example 3 Co-initiation of ⁇ -lactam monomer MM and ⁇ -lactam monomer with 2-(tritylthio)acetic acid-N-succinimidyl ester and lithium hexamethyldisilazide Preparation of random ⁇ -amino acid copolymers by CH
  • the experimental method is the same as that in Example 2, except that 1.2mL NM (0.2M) and 0.8mL CP (0.2M) are kept at the same concentration as 1.2mL MM and 0.8mL CH.
  • a random ⁇ -amino acid copolymer was finally obtained (75% yield, 21mer chain length as characterized by GPC).
  • Example 4 2-(Tritylthio)acetic acid-N-succinimidyl ester and lithium hexamethyldisilazide co-initiated ⁇ -lactam monomer DM and ⁇ -lactam monomer Preparation of random ⁇ -amino acid copolymers by CH
  • the experimental method is the same as that in Example 2, except that 1.2 mL of NM (0.2M) and 0.8 mL of CP (0.2M) are kept in the same concentration as 1.2 mL of MM and 0.8 mL of CO. Finally, random ⁇ -amino acid copolymer was obtained (the yield was 85%, and the chain length was 19mer as characterized by GPC).
  • Example 5 Co-initiation of ⁇ -lactam monomer MM and ⁇ -lactam monomer with 2-(tritylthio)acetic acid-N-succinimidyl ester and lithium hexamethyldisilazide Preparation of random ⁇ -amino acid copolymers by CH
  • the experimental method is the same as in Example 2, except that the concentration of NM (0.2M) and 0.8mL CP (0.2M) is not changed to 1.2mL DM and 0.8mL CH. Finally, random ⁇ -amino acid copolymer was obtained (the yield was 85%, and the chain length was 22mer as characterized by GPC).
  • Example 6 2-(Tritylthio)acetic acid-N-succinimidyl ester and lithium hexamethyldisilazide co-initiated ⁇ -lactam monomer MM and ⁇ -lactam monomer Preparation of random ⁇ -amino acid copolymers with CO
  • the experimental method was the same as in Example 5, except that 1.2 mL of NM (0.2M) and 0.8 mL of CP (0.2M) were kept in concentration and not changed to 1 mL of DM and 1 mL of CO. Finally, random ⁇ -amino acid copolymer was obtained (the yield was 79%, and the chain length was 21mer as characterized by GPC).
  • Example 7 2-(Tritylthio)acetic acid-N-succinimidyl ester and lithium hexamethyldisilazide co-initiated benzyl N-chloroformate- ⁇ -lactam-DL- Preparation of random ⁇ -amino acid copolymers from lysine and ⁇ -lactam monomer CH
  • the experimental method is the same as in Example 5, except that 1.2mL of NM (0.2M) and 0.8mL of CP (0.2M) are kept in concentration and not changed to be replaced by 1.4mL of benzyl chloroformate- ⁇ -lactam-L -Lysine) and 0.6 mL CH.
  • a random ⁇ -amino acid copolymer was finally obtained (82% yield, 18mer chain length as characterized by GPC).
  • Example 8 Initiation of N- ⁇ -tert-butoxycarbonyl-L-lysine-N-carboxy intracyclic anhydride and DL- ⁇ -glycine N-carboxythiocarbonyl intracyclic anhydride by 2-tritylmercaptoethylamine Preparation of random ⁇ / ⁇ -amino acid copolymers
  • N-dimethylformamide was the solvent.
  • Example 9 Initiation of N- ⁇ -tert-butoxycarbonyl-L-lysine-N-carboxy intracyclic acid anhydride and DL- ⁇ -phenylalanine N-carboxythiocarbonyl by 2-tritylmercaptoethylamine Preparation of Random ⁇ / ⁇ -Amino Acid Copolymers from Intracyclic Acid Anhydrides
  • the experimental method is the same as in Example 8, except that DL- ⁇ -glycine N-carboxythiocarbonyl intracyclic acid anhydride (0.2M) was kept at the same concentration, and replaced with DL- ⁇ -phenylalanine N-carboxythiol Carbonyl ring anhydride. Finally, a random ⁇ / ⁇ -amino acid copolymer was obtained (the yield was 75%, and the chain length characterized by GPC was 22mer)
  • Example 10 Preparation of oxazoline copolymer by 3-triphenylmethylpropyl bromide initiation of N- ⁇ -tert-butoxycarbonyl-2-(aminopropyl)oxazoline and 2-(cyclohexyl)oxazoline
  • reaction flask was sealed, taken out of the glove box, stirred at 140°C for 18 hours, and a small amount of the reaction solution was obtained using GPC standard to obtain the relative molecular weight and PDI; then cooled to room temperature and added cold petroleum ether (45mL), wait for white flocculent precipitation After precipitation, centrifugation was carried out to collect, then dissolved in tetrahydrofuran (2 mL), and precipitated with cold petroleum ether. After repeating this for three times, a polymer with a side chain protection was obtained. Then, trifluoroacetic acid (2 mL) and 40 uL of triethylsilane were added to the polymer, and the protective group was removed by shaking for 6 hours.
  • Example 11 Preparation of oxazoline copolymer by 3-triphenylmethylpropyl bromide initiation of N- ⁇ -tert-butoxycarbonyl-2-(aminopropyl)oxazoline and 2-(isobutyl)oxazoline
  • the experimental method is the same as in Example 10, except that 1.2 mL of 2-(cyclohexyl) oxazoline is replaced with 2-(isobutyl) oxazoline, and the amount of initiator and monomer is changed according to the molar ratio, Make the polymer theoretical chain length 20mer.
  • the oxazoline copolymer was finally obtained (the yield was more than 80%, and the chain length was 20 ⁇ 2mer as characterized by GPC)
  • Example 12 Adhesion test of ⁇ -amino acid polymers to osteoblasts
  • MC-3T3- MC-3T3- was cultured in ⁇ -MEM medium containing 10% fetal bovine serum (FBS), 1% penicillin and streptomycin, and 2 mM L-glutamine under 5% CO at 37°C. E1 osteoblasts. When the cells are observed to proliferate to cover 80-90% of the area of the entire dish, detach the cells from the dish using trypsin, remove the supernatant by centrifugation, and resuspend in medium to a final cell concentration of 105 cells/mL.
  • FBS fetal bovine serum
  • penicillin and streptomycin 1% penicillin and streptomycin
  • 2 mM L-glutamine under 5% CO at 37°C. E1 osteoblasts.
  • Example 2 10 ⁇ L of cell suspension was added to each individual slide of the ⁇ -amino acid polymer-modified anti-cell adhesion layer prepared in Example 1 (a layer of ⁇ -amino acid polymer was coated on the slide with anti-cell adhesion layer).
  • the wells in which the surface of the ⁇ -amino acid polymer was not modified were used as controls. Place the slides in a petri dish and incubate at 37 °C for 2 h to allow cells to reach initial attachment, then add fresh medium to the dish to submerge the entire slide, and incubate the slides at 37 °C Incubate for 1 day.
  • Example 13 Adhesion test of ⁇ -amino acid polymer and ⁇ / ⁇ -amino acid copolymer to osteoblasts
  • the implementation method is the same as that in Example 12, except that the ⁇ -amino acid polymer prepared in Examples 2-7 and the ⁇ / ⁇ -amino acid copolymer prepared in Examples 8-9 were modified to a glass slide with an anti-cell adhesion layer. On the surface of the sheet, ⁇ -amino acid polymer was replaced by ⁇ -amino acid polymer, ⁇ / ⁇ -amino acid copolymer.
  • the implementation method is the same as that in Example 12, except that the surface of the glass slide with the anti-cell adhesion layer was modified with the polypeptide-mimicking polymer prepared in Example 10, and the ⁇ -amino acid polymer was replaced with a polypeptide-mimicking polymer.
  • Example 15 Adhesion test of ⁇ -amino acid polymers to stem cells
  • the implementation method is the same as that in Example 12, except that MC-3T3-E1 osteoblasts are used instead of bone marrow mesenchymal stem cells.
  • Example 16 Adhesion test of ⁇ -amino acid polymer and ⁇ / ⁇ -amino acid copolymer to stem cells
  • the implementation method is the same as that of Example 13, except that MC-3T3-E1 osteoblasts are used to replace bone marrow mesenchymal stem cells.
  • Example 17 Adhesion test of amino acid polymer mimics to stem cells
  • the implementation method is the same as that of Example 14, except that MC-3T3-E1 osteoblasts are used to replace bone marrow mesenchymal stem cells.
  • Example 18 Proliferation test of ⁇ -amino acid polymers on osteoblasts
  • MC-3T3- MC-3T3- was cultured in ⁇ -MEM medium containing 10% fetal bovine serum (FBS), 1% penicillin and streptomycin, and 2 mM L-glutamine under 5% CO at 37°C. E1 osteoblasts.
  • FBS fetal bovine serum
  • penicillin and streptomycin 1% penicillin and streptomycin
  • 2 mM L-glutamine under 5% CO at 37°C. E1 osteoblasts.
  • Example 19 Proliferation test of ⁇ -amino acid polymer and ⁇ / ⁇ -amino acid copolymer on osteoblasts
  • the implementation method is the same as that of Example 18, except that the ⁇ -amino acid polymer is replaced by the ⁇ -amino acid polymer prepared in Examples 2-7 and the ⁇ / ⁇ -amino acid copolymer prepared in Examples 8-9.
  • the implementation method is the same as that of Example 18, except that the ⁇ -amino acid polymer is replaced with the amino acid polymer mimic prepared in Example 10.
  • Example 21 Migration assay of ⁇ -amino acid polymers on osteoblasts
  • MC-3T3- MC-3T3- was cultured in ⁇ -MEM medium containing 10% fetal bovine serum (FBS), 1% penicillin and streptomycin, and 2 mM L-glutamine under 5% CO at 37°C. E1 osteoblasts. When the cells are observed to proliferate to cover 80-90% of the area of the entire dish, cells are detached from the dish using trypsin, the supernatant is removed by centrifugation, and then resuspended in medium to a final cell concentration of 104 cells /mL.
  • FBS fetal bovine serum
  • penicillin and streptomycin 1% penicillin and streptomycin
  • 2 mM L-glutamine under 5% CO at 37°C. E1 osteoblasts.
  • Example 22 Migration test of ⁇ -amino acid polymers, ⁇ / ⁇ -amino acid copolymers on osteoblasts
  • the implementation method is the same as that of Example 21, except that the ⁇ -amino acid polymer is replaced by the ⁇ -amino acid polymer prepared in Examples 2-7 and the ⁇ / ⁇ -amino acid copolymer prepared in Examples 8-9.
  • the implementation method is the same as that of Example 18, except that the ⁇ -amino acid polymer is replaced with the amino acid polymer mimic prepared in Example 10.
  • the observation results showed that the 12h result showed that the migration speed of MC-3T3-E1 osteoblasts on the surface of the amino acid polymer mimic was comparable to that of the RGD modified surface, and both were faster than the KRSR modified surface; The osteocytes have completely covered the artificially set scratches, and the KRSR surface is not completely covered.
  • the surface modified by amino acid polymer mimics and RGD is beneficial to the migration of MC-3T3-E1 osteoblasts, which is superior to the osteogenic selective polypeptide KRSR.
  • Example 24 In vivo osteogenic activity test of ⁇ -amino acid polymer-modified PEG hydrogels
  • the experiment was evaluated using an orthotopic skull defect model.
  • the experimental animals were eight-week-old female SD rats with a mass of about 180 g-200 g, and the rats were anesthetized by intraperitoneal injection with sodium pentobarbital at a concentration of 40 mg/kg.
  • the rat was fixed on the operating table, and the head was shaved and disinfected with iodophor.
  • a wound of about 5-8 mm was incised with a knife in the middle of the head, and a circular defect with a diameter of 5 mm was created in the skull with an electric drill with a drill bit of 5 mm in diameter.
  • the defect is a full-thickness defect but does not damage the dura.
  • the PEG hydrogel is formed by mixing four-arm PEG with an acrylate end group and a four-arm PEG with a sulfhydryl group at the end group.
  • the hydrogel modified by ⁇ -amino acid polymer is composed of four-arm PEG whose end group is acrylate and ⁇ -amino acid polymer whose end group is thiol for 1 hour at room temperature. After the polymer is grafted to the end of part of PEG. Then it is mixed with four-arm PEG whose end group is sulfhydryl to form a gel.
  • Example 25 In vivo osseointegration activity test of ⁇ -amino acid polymer-modified titanium alloy implants
  • the experiment was evaluated using a femoral defect model.
  • the experimental animals were eight-week-old female SD rats with a mass of about 180 g-200 g, and the rats were anesthetized by intraperitoneal injection with sodium pentobarbital at a concentration of 40 mg/kg.
  • the rat was fixed on the operating table, and the legs were shaved and disinfected with iodophor.
  • Use a scalpel to cut a 5-8mm wound at the joint of the hind leg of the rat, and then use a knife to cut the muscle tissue at the cancellous bone of the distal femur, and use a peeler to poke the muscle of the cancellous bone to expose the bone.
  • modified titanium alloy bone nails For modified titanium alloy bone nails, the nails were first cleaned in a UV/O3 cleaning machine and then modified with polydopamine coating, and then the nails were immersed in RGD polypeptide or ⁇ -amino acid polymer solution for overnight reaction to obtain RGD polypeptide or ⁇ -amino acid polymer solution. Amino acid polymer modified titanium alloy bone nail.
  • results showed that the quantitative results of Micro-CT, histological staining results and biomechanical results showed that the experimental group of titanium alloy bone nails modified by ⁇ -amino acid polymer was different from the unmodified titanium alloy bone nails and the titanium alloy modified with RGD polypeptide. Compared with the experimental group of bone nails, the experimental group of titanium alloy bone nails modified by ⁇ -amino acid polymer significantly improved the osseointegration effect of the implant.
  • Example 26 In vivo osseointegration activity test of ⁇ -amino acid polymer-modified stainless steel implants
  • the experimental method is the same as that of Example 5, except that the titanium alloy bone screw is replaced with a stainless steel bone screw.
  • stainless steel bone nails to be modified with RGD polypeptide or ⁇ -amino acid polymer firstly wash the nails in a UV/O3 cleaning machine and then modify the polydopamine coating, and then immerse the nails in RGD polypeptide or polymer solution for overnight reaction to obtain RGD polypeptide or polymer modified stainless steel bone nail.
  • Example 27 Test of large fractured bone repairing activity of ⁇ -amino acid polymer-modified tobermorite implants
  • the experiment was evaluated using a large fractured bone defect model.
  • the experimental animals were eight-week-old female SD rats with a mass of about 180 g-200 g, and the rats were anesthetized with sodium pentobarbital at a concentration of 40 mg/kg by intraperitoneal injection.
  • the rat was fixed on the operating table, and the legs were shaved and disinfected with iodophor.
  • a 5-8mm wound was cut at the joint site of the hind leg of the rat with a scalpel, and then the muscle tissue was cut in the middle of the thigh with a knife, and the muscle at the site was opened with a peeler to expose the bone.
  • a polydopamine coating was first modified on the scaffold, and then immersed in a ⁇ -amino acid polymer solution for overnight reaction to obtain a ⁇ -amino acid polymer-modified tobermorite scaffold.

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Abstract

本发明公开了氨基酸聚合物或多肽模拟聚合物在骨修复或填充、置换中的应用，用于修饰骨植入材料表面或掺杂于其内部；或者用于制备骨修复或填充、置换材料。本发明的氨基酸聚合物或多肽模拟聚合物可大量制备、价格便宜，其本身、或者作为生物活性分子，用于修饰骨植入材料表面或掺杂于其内部，能够促进骨修复相关细胞的细胞粘附、增殖、迁移、分化等功能，从而促进成骨修复效果和骨整合效果。

Description

氨基酸聚合物或多肽模拟聚合物在骨修复中的应用 技术领域
本发明涉及骨修复材料领域，具体涉及氨基酸聚合物及多肽模拟聚合物在骨修中的应用。
背景技术
全世界每年因机械创伤、骨折、肿瘤切除或发育畸形等造成骨缺损的患者数以万计。自体或异体移植是目前临床上最为常用且有效的修复手段。但是自体骨移植会给患者带来二次创伤和高昂的治疗费用，异体移植存在一定的免疫排异反应，且来源有限无法满足极大的临床需求。因此，采用天然生物材料或人造生物材料来替代自体移植已经成为了另一个重要途径。
早期的骨修复材料主要为天然生物材料，来源于生物体内，生物相容性较好，但是有免疫原性、可能携带病菌、批次之间组分不稳定等诸多缺点限制了它们的应用。随着科技的发展，人工材料不断涌现，可以克服天然材料的很多缺点，但是生物活性差是制约其发展的瓶颈。生物活性材料的首要前提是能够支持细胞的粘附，从而才能实现细胞的增殖、迁移、分化等一系列生理活动。为了将生物惰性材料转变为生物活性材料，通常需要在惰性材料表面修饰一层活性分子，以促进细胞粘附从而提高组织相容性。在生物体内，细胞主要通过膜上的一些受体与细胞外基质蛋白(ECM蛋白)相结合来实现细胞粘附，其中在ECM蛋白中存在一些特定序列的活性多肽(例如：RGD，KRSR)。将具有细胞粘附功能的蛋白/多肽修饰于植入材料表面可以提高材料的细胞粘附效果，但是天然蛋白/多肽在生物体内容易降解，而骨组织修复是一个较为漫长的过程，并且价格昂贵，难以大量生产这极大的限制了其在临床中的运用。
因此，本领域亟需开发一种具有良好细胞粘附和骨修复功能同时制备简单、价格便宜，体内稳定性好甚至降解可调节的新材料。
发明内容
本发明的目的在于具有良好细胞粘附和骨修复功能同时制备简单、价格便宜，体内稳定性好甚至降解可调节的材料。
本发明提供一种氨基酸聚合物、多肽模拟聚合物或其药学上可接受的盐的应用，用于修饰骨植入材料表面或掺杂于其内部；或者用于制备骨修复材料。
在本发明中，氨基酸聚合物与多肽聚合物具有相同的含义。
在本发明中，多肽聚合物模拟物与多肽模拟聚合物具有相同的含义。
在本发明中，骨修复包括骨填充、骨置换。
在另一优选例中，所述氨基酸聚合物或多肽模拟聚合物或其药学上可接受的盐用作骨修复相关的活性分子，在骨植入材料内部掺杂或者在骨植入材料表面进行修饰，用于促进骨植入材料的骨整合效果。
在另一优选例中，所述氨基酸聚合物或多肽模拟聚合物物或其药学上可接受的盐用于制备成支架材料，用于骨修复。
本发明的氨基酸聚合物或多肽模拟聚合物或其药学上可接受的盐，在上述应用过程中，能够促进骨修复相关细胞的细胞粘附、增殖、迁移、分化等功能，从而促进成骨修复效果和骨整合效果。其中与骨修复相关的细胞为成骨细胞、前成骨细胞、干细胞、巨噬细胞中的一种或两种以上的组合。
在另一优选例中，所述骨植入材料包括骨填充材料、骨置换材料。
在另一优选例中，所述骨植入材料为不可降解的永久植入材料或可降解的植入材料。
在另一优选例中，所述不可降解的永久植入材料选自：钛、多孔钛、钛合金、钛镍合金、钽金属、镁金属、镁合金、不锈钢、钴铬合金、聚甲基丙烯酸甲酯、聚氨酯、聚醚醚酮、聚丙烯酰胺、聚乙烯醇。
在另一优选例中，所述可降解的植入材料选自：聚乳酸、聚(乳酸-羟基乙酸)共聚物、聚丙交酯、聚乙交酯、聚乙丙交酯、聚己内酯、聚已酸内酯、氧化铝、氧化锆、羟基磷灰石、磷酸三钙、生物玻璃、胶原、透明质酸、壳聚糖、海藻酸盐、丝素蛋白、纤维蛋白、明胶、纤维素。
在另一优选例中，所述骨植入材料为惰性植入材料。
在另一优选例中，所述骨修复材料的形式为水凝胶、电纺膜、3D打印支架、多孔支架、实心支架、骨水泥、可注射骨材料、体内交联骨材料、复合材料中的一种或两种以上的组合。
在另一优选例中，所述氨基酸聚合物或多肽模拟聚合物为选自下组的一种或两种以上的均聚物、二元共聚物或多元共聚物：α-氨基酸、β-氨基酸、γ-氨基酸、噁唑啉。
在另一优选例中，所述氨基酸聚合物或多肽模拟聚合物为噁唑啉聚合物、α-氨基酸聚合物、α/β-氨基酸聚合物、γ-氨基酸聚合物或β-氨基酸聚合物。
在另一优选例中，所述氨基酸聚合物或多肽模拟聚合物为以下Aa、Aa’、Bb、Bb’、Cc、Cc’、Cc”、Dd、Dd’、Ee、Ee’、Ff、Ff’和Gg结构组成的均聚物、二元共聚物或多元共聚物，重复单元总数为5-5000的正整数：
Figure PCTCN2021131541-appb-000001
Figure PCTCN2021131541-appb-000002
其中，r在各出现处独立地为0、1、2、3、4或5；r'在各出现处独立地为1、2或3；r”在各出现处独立地为0、1、2或3；
式中的R 1、R 2、R 3、R 4、R 5和R 6在出现处分别各自独立地选自以下基团：氢、C1-C6烷基、C1-C6卤代烷基、C1-C6烷基羟基、C1-C6烷氧基、C1-C6烷基磺酰基、C1-C6烷基胍基、C1-C6烷基酯基、硫代C1-C6烷基酯基、C2-C6烯基、C2-C6炔基、C3-C12环烷基、C6-C12芳基、5-12元杂芳基、5-12元杂环基、C1-C6烷基-C6-C12芳基、氨基和
Figure PCTCN2021131541-appb-000003
P 1为保护基，在各出现处独立地选自以下基团：叔丁氧羰基(Boc)、苄氧羰基(Cbz)、芴甲氧羰基(Fmoc)、邻苯二甲酰基(Pht)、乙酰基(Ac)、三氟乙酰基(Tfa)、苄基(Bn)、三苯基甲基(Tr)；
P 2在各出现处独立地选自以下基团：氢、取代或未取代的C1-C6烷基、取代或未取代的C6-C12芳基、取代或未取代的5-12元杂芳基、取代或未取代的5-12元杂环基；
X在各出现处独立地选自以下基团：无、氢、氨基、胍基、羟基、羧基、酰氨基、巯基、甲硫基、烯基、炔基、酯基、芳基或5-12元杂环基；
L在各出现处独立地选自：-CHR' 1-、-CO-、-COO-、-S(＝O) 2-；q为0-6的整数；
R' 1在各出现处独立地选自取代或未取代的以下基团：氢、氨基、C1-C15烷基、C1-C15烷基氨基、C1-C15烷基羟基、C1-C15烷基醛基、C1-C15烷基酯基、硫代C1-C15烷基酯基、C6-C15芳基、C2-C15烯基、C2-C15炔基、-Rc-COO-Rc”、-Rc-CO-Rc”、-Rc-O-Rc”-、-Rc-S-Rc”、5-15元杂芳基、5-12元杂环基；
R a和R b在各出现处各自独立地选自取代或未取代的以下基团：不存在、氢、C1-C15烷基、C1-C15烷基氨基、C1-C15烷基羟基、C1-C15烷基醛基、C1-C15烷基磺酰基、C2-C15烯基、C2-C15炔基、-Rc-COO-Rc”、-Rc-CO-Rc”、-Rc-O-Rc”-、-Rc-S-Rc”、C3-C12环烷基、C4-C12环烯基、5-12元杂环基、C6-C12芳基、5-12元杂芳基；
Rc在出现处分别各自独立地选自取代或未取代的以下基团：无、C1-C15亚烷基、C2-C15亚烯基、C2-C15亚炔基、C3-C12亚环烷基、C4-C12亚环烯基、3-12元亚杂环基、C6-C12亚芳基、5-12元亚杂芳基；
Rc”在出现处分别各自独立地选自取代或未取代的以下基团：C1-C15烷基、C1-C15烷基氨基、C2-C15烯基、C2-C15炔基、C3-C12环烷基、C4-C12环烯基、3-12元杂环基、C6-C12芳基、5-12元杂芳基，
上述各取代独立地指被选自以下一个或多个取代基取代：卤素、羟基、氨基、苯基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C3-C8环烷基。
在另一优选例中，重复单元总数为为5-100较佳为5-50。
在另一优选例中，R 1、R 2、R 3、R 4、R 5和R 6在出现处分别各自独立地选自以下基团：氢、C1-C4烷基、C1-C4卤代烷基、C1-C4烷基羟基、C1-C4烷氧基、C1-C4烷基磺酰基、C1-C4烷基胍基、C1-C4烷基酯基、硫代C1-C4烷基酯基、C2-C4烯基、C2-C4炔基、C3-C6环烷基、苯基、萘基、5-6元杂芳基、5-6元杂环基、C1-C4烷基-C6芳基、氨基和
Figure PCTCN2021131541-appb-000004
在另一优选例中，X在出现处各自独立选自以下基团：无、氢、氨基、胍基、羟基、羧基、酰氨基、巯基、甲硫基、烯基、炔基、酯基(-COO-)、苯基或5-6元杂环基。
在另一优选例中，L在出现处各自独立选自：-CH 2-、-CO-、-COO-。
在另一优选例中，q为0、1、2、3、4或5。当q为0时，(L)q不存在。
在另一优选例中，Ra和Rb在出现处各自独立地选自取代或未取代的下组基团：不存在、氢、C1-C6烷基、C1-C6烷基氨基、C1-C6烷基羟基、C1-C6烷基醛基、C1-C6烷基磺酰基、C2-C6烯基、C2-C6炔基、-Rc-COO-Rc”、-Rc-CO-Rc”、-Rc-O-Rc”-、-Rc-S-Rc”、C3-C6环烷基、C4-C6环烯基、5-6元杂环基、苯基、5-6元杂芳基。
在另一优选例中，所述药学上可接受的盐为所述氨基酸聚合物或多肽模拟聚合物的盐酸盐、溴酸盐、三氟乙酸盐、磷酸盐、锂盐、钠盐、或钾盐。
在另一优选例中，A、A’、B、B’、C、C’、D、D’、E、E’、F、F’和G结构所示出氨基酸是L构型、D构型、或者D构型L构型两者的混合。
在另一优选例中，所述共聚物为无规共聚物、交替共聚物或嵌段共聚物。较佳地，为无规共聚物。
本发明氨基酸聚合物或多肽模拟聚合物还包括氨基酸聚合物或多肽模拟聚合物衍生物，所述衍生物是指聚合物侧链的氨基变成其他官能团比如胍基等，或侧链含有的氨基通过化学反应而连接其他分子，比如药物分子、荧光小分子、保护基等；聚合物的末端进行化学修饰，比如连接荧光分子，或者药物分子。
在另一优选例中，所述氨基酸聚合物或多肽模拟聚合物选自：
Figure PCTCN2021131541-appb-000005
Figure PCTCN2021131541-appb-000006
式中，n为5-5000的正整数；a为0-100的正整数；
0％＜x≤100％,0％≤y≤100％，且x+y＝100％；
R z选自：卤素、羧基、活性酯基团、酰氯、环氧烷、巯基、C2-C15烯烃基团、C2-C15炔基、叠氮、马来酰亚胺、邻二硫吡啶基(OPSS)、环糊精、金刚烷；
R s在出现处分别各自独立地为氢或
Figure PCTCN2021131541-appb-000007
R t在各出现处各自独立地选自以下基团：C1-C15烷基、C1-C15烷基氨基、C2-C15烯基、C2-C15炔基、C3-C12环烷基、C4-C12环烯基、3-12元杂环基、C6-C12芳基、5-12元杂芳基；
Rw为
Figure PCTCN2021131541-appb-000008
波浪线表示连接处；A’为0-12的正整数；式中的R 11、R 12、R 13和R 14在出现处分别各自独立地选自以下基团：氢、C1-C6烷基、C1-C6卤代烷基、C1-C6烷基羟基、C1-C6烷氧基、C1-C6烷基磺酰基、C1-C6烷基胍基、C1-C6烷基酯基、硫代C1-C6烷基酯基、C2-C6烯基、C2-C6炔基、C3-C12环烷基、C6-C12芳基、5-12元杂芳基、5-12元杂环基、C1-C6烷基-C6-C12芳基、氨基和
Figure PCTCN2021131541-appb-000009
P 1为保护基，在各出现处独立地选自以下基团：叔丁氧羰基(Boc)、苄氧羰基(Cbz)、芴甲氧羰基(Fmoc)、邻苯二甲酰基(Pht)、乙酰基(Ac)、三氟乙酰基(Tfa)、苄基(Bn)、三苯基甲基(Tr)；
P 2在各出现处独立地选自以下基团：氢、取代或未取代的C1-C6烷基、取代或未取代的C6-C12芳基、取代或未取代的5-12元杂芳基、取代或未取代的5-12元杂环基；
上述各取代独立地指被选自以下一个或多个取代基取代：卤素、羟基、氨基、苯 基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C3-C8环烷基。
在另一优选例中，以上结构单元中氨基酸是L构型、D-构型、或者D构型和L构型的混合。
在另一优选例中，上述结构阴离子选自：Cl -、Br -、CF 3COO -、H 2PO 4 -、HPO 4 2-、PO 4 3-。
本发明中，x和y分别为各个组分的比例，x和y的计算方式为相对应组分的重复单元数除以氨基酸聚合物或多肽模拟聚合物重复单元总数。
在另一优选例中，所述氨基酸聚合物或多肽模拟聚合物选自：
Figure PCTCN2021131541-appb-000010
式中，n为5-5000的正整数；a为0-100的正整数；
0％＜x≤100％,0％≤y≤100％，且x+y＝100％；
R z选自：卤素、羧基、活性酯基团、酰氯、环氧烷、巯基(-SH)、C2-C15烯烃基团、C2-C15炔基、叠氮、马来酰亚胺、邻二硫吡啶基(OPSS)、环糊精、金刚烷中的任意一种。
在另一优选例中，以上结构单元中氨基酸是L构型、D-构型、或者D构型和L构型的混合。
在另一优选例中，上述结构阴离子选自：Cl -、Br -、CF 3COO -、H 2PO 4 -、HPO 4 2-、PO 4 3-。
在另一优选例中，上述聚合物结构中的两重复单元的排列形式为无规、交替或者嵌段形式，较佳地，为无规形式。
在另一优选例中，n为5-100较佳为5-50。
在另一优选例中，x：y为0.01：0.99至0.99:0.01，较佳为0.05:0.95至0.95:0.05，甚至1:9至9:1。
本发明的主要优点包括：
(1)本发明提供了一种易于大规模合成、价格便宜、体内稳定性高或稳定性可调整的支持骨修复相关细胞粘附和骨修复及骨整合的材料或材料组合物；
(2)本发明提供的支持细胞粘附等活性功能的材料或材料组合物(氨基酸聚合物及多肽模拟聚合物)无需特定氨基酸序列即可获得骨修复相关细胞的细胞粘附等功能，并能媲美细胞粘附黄金标准RGD多肽。
(3)本发明提供的支持细胞粘附的材料或材料组合物(氨基酸聚合物及多肽模拟聚合物)能够显著提高惰性材料的细胞粘附等功能，促进材料与骨组织的相容性，实现较好的骨整合和骨修复效果，具有巨大的临床应用优势和价值；
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件(如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press，1989)中所述的条件)或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
α-氨基酸聚合物的制备
实施例1：六甲基二硅基胺基锂盐(LiHMDS)引发DL-正亮氨酸-N-羧基环内酸酐和N-ε-叔丁氧羰基-DL-赖氨酸-N-羧基环内酸酐的无规敞口条件共聚
Figure PCTCN2021131541-appb-000011
将六甲基二硅基胺基锂盐(33.4mg，0.2mmol)准确称量，并用四氢呋喃(2mL)配置成0.1M浓度的溶液，备用。将DL-正亮氨酸-N-羧基环内酸酐(7.9mg，0.05mmol)和N-ε-叔丁氧羰基-DL-赖氨酸-N-羧基环内酸酐(20.4mg，0.075mmol)(单体比例6：4)准确称量，用四氢呋喃(1mL)溶解于装有搅拌子的反应瓶中。在搅拌的反应瓶中，加入0.25mL浓度为0.1M的六甲基二硅基胺基锂盐溶液。将混合物在手套箱中室温下搅拌反应5分钟。聚合反应结束后使用三苯基巯基乙胺进行封端过夜。在上述反应混合物中倒入冷石油醚(40mL)，析出的白色絮状物经离心收集，在气流中干燥，并重新溶于四氢呋喃(1.5mL)中，再加入大量冷石油醚沉淀。这个溶解-沉淀过程共重复三次，得到纯化的共聚物。将抽干的聚合物加入2mL三氟乙酸和5％(v/v)三乙基硅烷，在室温下轻晃动过夜后吹掉多余的三氟乙酸，得到的粘稠状液体溶于0.5mL甲醇，后加入45mL冰冻乙醚使之析出白色沉淀，溶解-沉淀过程重复三次，从而得到侧链氨基脱保护的无规聚合物。脱保护的聚合物再次用5mL超纯水溶解，过滤冻干后用于接下来的生物活性测试。(产率80％,GPC表征链长为32mer)
β-氨基酸聚合物的制备
实施例2：2-(三苯甲基硫代)乙酸-N-琥珀酰亚胺酯和六甲基二硅基胺基锂盐共引发β-内酰胺单体NM和β-内酰胺单体CP制备无规β-氨基酸共聚物
Figure PCTCN2021131541-appb-000012
在氮气保护的手套箱内，称NM和CP，以干燥的THF(四氢呋喃)为溶剂，在反应瓶中加入磁子，取1.2mL NM(0.2M)和0.8mL CP(0.2M)进行搅拌。然后分别配置对2-(三苯甲基硫代)乙酸-N-琥珀酰亚胺酯(0.2M)和六甲基二硅基胺基锂盐(0.5M)作为共引发剂,各取100uL迅速加入反应瓶中。室温反应4小时，从手套箱内取出反应瓶加1滴甲醇淬灭。在反应液中加入石油醚(45mL)，待白色絮状沉淀析出后进行离心收集，再用THF(1mL)溶解，并用石油醚沉淀。如此重复三次后，得到带保护的聚合物。然后在带保护的聚合物中加入三氟乙酸(2mL)后震荡2小时脱去保护基团，吹去大部分三氟乙酸后，加冰甲基叔丁基醚(50mL)析出白色沉淀后离心收集，再用甲醇(1mL)溶解，并用冰乙醚(50mL)沉淀，如此重复三次后，用油泵抽干剩余溶剂，再 分别用超纯水(5mL)溶解样品，最后冻干获得脱保护后的无规β-氨基酸共聚物(产率80％,GPC表征链长为20mer)。
实施例3：2-(三苯甲基硫代)乙酸-N-琥珀酰亚胺酯和六甲基二硅基胺基锂盐共引发β-内酰胺单体MM和β-内酰胺单体CH制备无规β-氨基酸共聚物
Figure PCTCN2021131541-appb-000013
实验方法同实施例2，不同之处为将1.2mL NM(0.2M)和0.8mL CP(0.2M)保持浓度不变换为1.2mL MM和0.8mL CH。最终获得无规β-氨基酸共聚物(产率75％，GPC表征链长为21mer)。
实施例4：2-(三苯甲基硫代)乙酸-N-琥珀酰亚胺酯和六甲基二硅基胺基锂盐共引发β-内酰胺单体DM和β-内酰胺单体CH制备无规β-氨基酸共聚物
Figure PCTCN2021131541-appb-000014
实验方法同实施例2，不同之处为将1.2mL NM(0.2M)和0.8mL CP(0.2M)保持浓度不变换为1.2mL MM和0.8mL CO。最终获得无规β-氨基酸共聚物(产率85％,GPC表征链长为19mer)。
实施例5：2-(三苯甲基硫代)乙酸-N-琥珀酰亚胺酯和六甲基二硅基胺基锂盐共引发β-内酰胺单体MM和β-内酰胺单体CH制备无规β-氨基酸共聚物
Figure PCTCN2021131541-appb-000015
实验方法同实施例2，不同之处为将NM(0.2M)和0.8mL CP(0.2M)保持浓度不变换为1.2mL DM和0.8mL CH。最终获得无规β-氨基酸共聚物(产率85％,GPC表征链长为22mer)。
实施例6：2-(三苯甲基硫代)乙酸-N-琥珀酰亚胺酯和六甲基二硅基胺基锂盐共引发β-内酰胺单体MM和β-内酰胺单体CO制备无规β-氨基酸共聚物
Figure PCTCN2021131541-appb-000016
实验方法同实施例5，不同之处为将1.2mL NM(0.2M)和0.8mL CP(0.2M)保持浓度不变换为1mL DM和1mL CO。最终获得无规β-氨基酸共聚物(产率79％,GPC表征链长为21mer)。
实施例7：2-(三苯甲基硫代)乙酸-N-琥珀酰亚胺酯和六甲基二硅基胺基锂盐共引发N-氯甲酸苄酯-β-内酰胺-DL-赖氨酸和β-内酰胺单体CH制备无规β-氨基酸共聚物
Figure PCTCN2021131541-appb-000017
实验方法同实施例5，不同之处为将1.2mL NM(0.2M)和0.8mL CP(0.2M)保持浓度不变换为换为1.4mL的N-氯甲酸苄酯-β-内酰胺-L-赖氨酸)和0.6mL CH。最终获得无规β-氨基酸共聚物(产率82％，GPC表征链长为18mer)。
α/β-氨基酸聚合物的制备
实施例8：2-三苯甲基巯基乙胺引发N-ε-叔丁氧羰基-L-赖氨酸-N-羧基环内酸酐和DL-β-甘氨酸N-羧基硫代羰基环内酸酐制备无规α/β-氨基酸共聚物
Figure PCTCN2021131541-appb-000018
在氮气保护的手套箱内，称N-ε-叔丁氧羰基-L-赖氨酸-N-羧基环内酸酐和DL-β-甘氨酸N-羧基硫代羰基环内酸酐，以干燥的N,N-二甲基甲酰胺为溶剂。先将磁子加入反应瓶，然后加1.2mL的N-ε-叔丁氧羰基-L-赖氨酸-N-羧基环内酸酐(0.2M)和0.8mL的 DL-β-甘氨酸N-羧基硫代羰基环内酸酐(0.2M)进行搅拌。称取引发剂2-三苯甲基巯基乙胺并配置成溶液(0.2M)，取100μL迅速加入反应瓶中，该反应在手套箱中室温搅拌反应3天，反应液从手套箱内取出，加入冷石油醚(45mL)，待白色絮状沉淀析出后进行离心收集，再用四氢呋喃(1mL)溶解，并用冷石油醚沉淀，如此重复三次后得到侧链带保护的聚合物。之后在聚合物中加入三氟乙酸(2mL)后震荡2小时脱去保护基团，吹去大部分三氟乙酸后，加冰甲基叔丁基醚(50mL)析出白色沉淀后离心收集，再用甲醇(1mL)溶解，并用冰乙醚(50mL)沉淀，如此重复三次后，用油泵抽干剩余溶剂，再用超纯水(5mL)溶解样品，最后冻干获得脱保护后的无规α/β-氨基酸共聚物(产率72.5％，GPC表征链长为19mer)
实施例9：2-三苯甲基巯基乙胺引发N-ε-叔丁氧羰基-L-赖氨酸-N-羧基环内酸酐和DL-β-苯丙氨酸N-羧基硫代羰基环内酸酐制备无规α/β-氨基酸共聚物
Figure PCTCN2021131541-appb-000019
实验方法同实施例8，不同之处为将DL-β-甘氨酸N-羧基硫代羰基环内酸酐(0.2M)保持浓度不变，换为DL-β-苯丙氨酸N-羧基硫代羰基环内酸酐。最终获得无规α/β-氨基酸共聚物(产率75％，GPC表征链长为22mer)
噁唑啉聚合物的制备
实施例10：3-三苯基甲基丙溴引发N-ε-叔丁氧羰基-2-(氨基丙基)噁唑啉和2-(环己基)噁唑啉制备噁唑啉共聚物
Figure PCTCN2021131541-appb-000020
在氮气保护的手套箱内，称N-ε-叔丁氧羰基-2-(氨基丙基)噁唑啉和2-(环己基)噁唑啉，以干燥的N,N-二甲基乙酰胺为溶剂。在反应瓶中加入磁子后分别称量并加入0.6mL(1M)的N-ε-叔丁氧羰基-2-(氨基甲基)噁唑啉和1.4mL(1M)2-(环己基)噁唑啉进行搅拌。然后配制引发剂3-三苯基甲基丙溴(1M)。最后将反应瓶密封后拿出手套箱后在140℃搅拌反应18小时，取少量反应液使用GPC标准得到相对分子量和PDI；然后冷却至室温后加入冷石油醚(45mL),待白色絮状沉淀析出后进行离心收集，再用四氢呋喃(2mL)溶解，并用冷石油醚沉淀，如此重复三次后得到侧链带保护的聚合物。之后在聚合物中加入三氟乙酸(2mL)和40uL的三乙基硅烷后震荡6小时脱去保护基团，吹去大部分三氟乙酸后，加冰甲基叔丁基醚(45mL)析出白色沉淀后离心收集，再用甲醇(1mL)溶解，并用冰乙醚(45mL)沉淀，如此重复三次后， 用油泵抽干剩余溶剂，再用超纯水(5mL)溶解样品，最后冻干获得脱保护后的噁唑啉共聚物(产率大于80％，GPC表征链长为30±2mer)。
实施例11：3-三苯基甲基丙溴引发N-ε-叔丁氧羰基-2-(氨基丙基)噁唑啉和2-(异丁基)噁唑啉制备噁唑啉共聚物
Figure PCTCN2021131541-appb-000021
实验方法同实施例10，不同之处在于将1.2mL的2-(环己基)噁唑啉换为2-(异丁基)噁唑啉，同时按照摩尔比改变引发剂和单体的量，使得聚合物理论链长为20mer。最终获得噁唑啉共聚物(产率大于80％，GPC表征链长为20±2mer)
实施例12：α-氨基酸聚合物对成骨细胞的粘附测试
在含10％胎牛血清(FBS)、1％青霉素和链霉素、2mM的L-谷氨酰胺的α-MEM培养基中，在5％CO 2和37℃环境下，培养MC-3T3-E1成骨细胞。观察待细胞增殖覆盖达到整个培养皿的面积的80-90％时，使用胰蛋白酶从培养皿中分离出细胞，离心去除上清液，然后重悬于培养基中，使最终细胞浓度为10 5细胞/mL。将10μL细胞悬浮液添加到实施例1制备的α-氨基酸聚合物修饰的抗细胞黏附层载玻片(在具有抗细胞黏附层载玻片上涂覆一层α-氨基酸聚合物)的每个单独的孔中，其中不修饰α-氨基酸聚合物的表面为对照。将载玻片放置在培养皿中，并在37℃下孵育2小时以使细胞达到初始附着，然后将新鲜培养基添加到培养皿中以浸没整个载玻片，并将载玻片在37℃下孵育1天。去除多余的培养基后，将细胞与含有2μM钙黄绿素AM和4μM溴乙啡锭二聚体-1的细胞死活染色溶液在黑暗中孵育15分钟。在显微镜下观察并拍摄每个孔的不同位置的细胞荧光图，并使用ImageJ软件分析图像。
观察结果表明，不修饰α-氨基酸聚合物的表面细胞几乎没有粘附，α-氨基酸聚合物修饰的表面，MC-3T3-E1成骨细胞具有良好的粘附铺展形态。
实施例13：β-氨基酸聚合物、α/β-氨基酸共聚物对成骨细胞的粘附测试
实施方法同实施例12，不同之处在于，使用实施例2-7制备的β-氨基酸聚合物、实施例8-9制备的α/β-氨基酸共聚物修饰到了具有抗细胞黏附层的载玻片表面，α-氨基酸聚合物替换成了β-氨基酸聚合物、α/β-氨基酸共聚物。
观察结果表明，未修饰聚合物的表面细胞几乎没有粘附，β-氨基酸聚合物、α/β-氨基酸共聚物修饰的表面，MC-3T3-E1成骨细胞具有良好的粘附铺展形态。
实施例14：多肽模拟聚合物对成骨细胞的粘附测试
实施方法同实施例12，不同之处在于，使用实施例10制备的多肽模拟聚合物修饰 具有抗细胞黏附层的载玻片表面，α-氨基酸聚合物替换成了多肽模拟聚合物。
观察结果表明，不修饰多肽模拟聚合物的表面细胞几乎没有粘附，多肽模拟聚合物修饰的表面，MC-3T3-E1成骨细胞具有良好的粘附铺展形态。
实施例15：α-氨基酸聚合物对干细胞的粘附测试
实施方法同实施例12，不同之处在于，使用MC-3T3-E1成骨细胞替换成了骨髓间充质干细胞。
观察结果表明，不修饰α-氨基酸聚合物的表面细胞几乎没有粘附，α-氨基酸聚合物修饰的表面，骨髓间充质干细胞具有良好的粘附铺展形态。
实施例16：β-氨基酸聚合物、α/β-氨基酸共聚物对干细胞的粘附测试
实施方法同实施例13，不同之处在于，使用MC-3T3-E1成骨细胞替换成了骨髓间充质干细胞。
观察结果表明，未修饰聚合物的表面细胞几乎没有粘附，β-氨基酸聚合物、α/β-氨基酸共聚物修饰的表面，骨髓间充质干细胞具有良好的粘附铺展形态。
实施例17：氨基酸聚合物模拟物对干细胞的粘附测试
实施方法同实施例14，不同之处在于，使用MC-3T3-E1成骨细胞替换成了骨髓间充质干细胞。
观察结果表明，不修饰氨基酸聚合物模拟物的表面细胞几乎没有粘附，氨基酸聚合物模拟物修饰的表面，骨髓间充质干细胞具有良好的粘附铺展形态。
实施例18：α-氨基酸聚合物对成骨细胞的增殖测试
在含10％胎牛血清(FBS)、1％青霉素和链霉素、2mM的L-谷氨酰胺的α-MEM培养基中，在5％CO 2和37℃环境下，培养MC-3T3-E1成骨细胞。观察待细胞增殖覆盖达到整个培养皿的面积的80-90％时，使用胰蛋白酶从培养皿中分离出细胞，离心去除上清液，然后重悬于培养基中，使最终细胞浓度为10 4细胞/mL。将100μL细胞悬浮液添加到实施例1制备的α-氨基酸聚合物、氨基、RGD多肽(细胞黏附肽的黄金标准)修饰的载玻片的每个单独的孔中。将载玻片放置在培养皿中，并在37℃下孵育2小时以使细胞达到初始附着，然后将新鲜培养基添加到培养皿中以浸没整个载玻片，并将载玻片在37℃下孵育1天，3天，5天。除去培养基后，向各孔中加入50μl的Alamar-Blue检测溶液，并在37℃避光条件下孵育3小时。随后将每个孔中的液体转移到黑色不透光的384孔板中，使用酶标仪在激发波长560nm、发射波长590nm处检测每孔的吸光度。
观察结果表明，第三天和第五天时，在α-氨基酸聚合物修饰的表面，MC-3T3-E1成骨细胞的增殖效果与细胞粘附黄金标准的RGD多肽修饰的表面上相当，并且都显著性高于氨基表面。
实施例19：β-氨基酸聚合物、α/β-氨基酸共聚物对成骨细胞的增殖测试
实施方法同实施例18，不同之处在于，α-氨基酸聚合物替换成了实施例2-7制备的β-氨基酸聚合物、实施例8-9制备的α/β-氨基酸共聚物。
观察结果表明，第三天和第五天时，在β-氨基酸聚合物、α/β-氨基酸共聚物修饰的 表面，MC-3T3-E1成骨细胞的增殖效果与细胞粘附黄金标准的RGD多肽修饰的表面上相当，并且都显著性高于氨基表面。
实施例20：氨基酸聚合物模拟物对成骨细胞的增殖测试
实施方法同实施例18，不同之处在于，α-氨基酸聚合物替换成了实施例10制备的氨基酸聚合物模拟物。
观察结果表明，第三天和第五天时，在氨基酸聚合物模拟物修饰的表面，MC-3T3-E1成骨细胞的增殖效果与细胞粘附黄金标准的RGD多肽修饰的表面上相当，并且都显著性高于氨基表面。
实施例21：α-氨基酸聚合物对成骨细胞的迁移测试
在含10％胎牛血清(FBS)、1％青霉素和链霉素、2mM的L-谷氨酰胺的α-MEM培养基中，在5％CO 2和37℃环境下，培养MC-3T3-E1成骨细胞。观察待细胞增殖覆盖达到整个培养皿的面积的80-90％时，使用胰蛋白酶从培养皿中分离出细胞，离心去除上清液，然后重悬于培养基中，使最终细胞浓度为104细胞/mL。将100μL细胞悬浮液添加到实施例1制备的α-氨基酸聚合物、KRSR多肽(成骨细胞选择性粘附多肽)、RGD多肽(细胞粘附黄金标准)修饰的载玻片的每个单独的孔中。将载玻片放置在培养皿中，并在37℃下孵育2小时以使细胞达到初始附着，然后将新鲜培养基添加到培养皿中以浸没整个载玻片，并将载玻片在37℃下培养1天。使用标准的100μL一次性移液枪头在每个培养细胞的孔中划一条直线，除去直线上黏附的MC-3T3-E1成骨细胞，并将载玻片在37℃下培养0h、12h、24h。去除多余的培养基后，将细胞与含有2μM钙黄绿素AM和4μM溴乙啡锭二聚体-1的细胞死活染色溶液在黑暗中孵育15分钟。在显微镜下观察并拍摄每个孔的不同位置的细胞荧光图，并使用ImageJ软件分析图像。
观察结果表明，12h结果表明，MC-3T3-E1成骨细胞在α-氨基酸聚合物表面与RGD修饰表面迁移速度相当，且都快于KRSR修饰的表面；24h结果表明，MC-3T3-E1成骨细胞已经完全覆盖人为设置划痕，KRSR表面未能完全覆盖。综上α-氨基酸聚合物和RGD修饰的表面有利于MC-3T3-E1成骨细胞的迁移，优于成骨选择性多肽KRSR。
实施例22：β-氨基酸聚合物、α/β-氨基酸共聚物对成骨细胞的迁移测试
实施方法同实施例21，不同之处在于，α-氨基酸聚合物替换成了实施例2-7制备的β-氨基酸聚合物、实施例8-9制备的α/β-氨基酸共聚物。
观察结果表明，12h结果表明，MC-3T3-E1成骨细胞在β-氨基酸聚合物、α/β-氨基酸共聚物表面与RGD修饰表面迁移速度相当，且都快于KRSR修饰的表面；24h结果表明，MC-3T3-E1成骨细胞已经完全覆盖人为设置划痕，KRSR表面未能完全覆盖。综上β-氨基酸聚合物、α/β-氨基酸共聚物和RGD修饰的表面有利于MC-3T3-E1成骨细胞的迁移，优于成骨选择性多肽KRSR。
实施例23：氨基酸聚合物模拟物对成骨细胞的迁移测试
实施方法同实施例18，不同之处在于，α-氨基酸聚合物替换成了实施例10制备的氨基酸聚合物模拟物。观察结果表明，12h结果表明，MC-3T3-E1成骨细胞在氨基酸聚合物模拟物表面与RGD修饰表面迁移速度相当，且都快于KRSR修饰的表面；24h结 果表明，MC-3T3-E1成骨细胞已经完全覆盖人为设置划痕，KRSR表面未能完全覆盖。综上氨基酸聚合物模拟物和RGD修饰的表面有利于MC-3T3-E1成骨细胞的迁移，优于成骨选择性多肽KRSR。
实施例24：β-氨基酸聚合物修饰PEG水凝胶的体内成骨活性测试
该实验采用原位颅骨缺损模型进行评价。实验动物为质量约180g-200g的八周雌性SD大鼠，使用浓度为40mg/kg的戊巴比妥钠通过腹腔注射麻醉大鼠。将大鼠固定于操作台，头部剃毛后用碘伏消毒。在头部正中部位用刀划开约5-8mm伤口，用带直径5mm钻头的电钻在颅骨部位造成直径为5mm的圆形缺损。该缺损为全层缺损但不损伤硬脑膜。在钻孔的过程中需用无菌生理盐水冲洗钻头以达到降温的效果避免过热造成骨组织的热损伤。最后，在18只大鼠中产生36个临界尺寸的颅骨缺损，并随机植入以下6组水凝胶材料：(1)含5wt％PEG的水凝胶材料(n＝6)；(2)实施例6制备的β-氨基酸聚合物修饰的5％PEG的水凝胶材料(n＝6)；(3)含10wt％PEG的水凝胶材料(n＝6)；(4)实施例6制备的β-氨基酸聚合物修饰的10wt％PEG的水凝胶材料(n＝6)；(5)含20wt％PEG的水凝胶材料(n＝6)；(6)实施例6制备的β-氨基酸聚合物修饰的20wt％PEG的水凝胶材料(n＝6)。材料植入后用可吸收缝线将切口缝合。手术后，允许动物自由获得鼠粮和水。植入八周后，通过腹腔注射过量的戊巴比妥钠处死大鼠。收集样品并用4％多聚甲醛溶液固定组织。使用Micro-CT定量分析每组植入材料的骨修复情况。
对于上述水凝胶材料，PEG水凝胶由端基为丙烯酸酯的四臂PEG和端基为巯基的四臂PEG混合成胶。β-氨基酸聚合物修饰的水凝胶是由端基为丙烯酸酯的四臂PEG先与端基为巯基的β-氨基酸聚合物室温下反应1小时，待聚合物接枝到部分PEG的末端后再与端基为巯基的四臂PEG混合成胶。
结果显示：对于三种不同PEG含量的水凝胶材料，都是加了β-氨基酸聚合物修饰的实验组的新生骨体积大于对应的不加β-氨基酸聚合物修饰的PEG水凝胶实验组。
实施例25：β-氨基酸聚合物修饰钛合金植入体的体内骨整合活性测试
该实验采用股骨缺损模型进行评价。实验动物为质量约180g-200g的八周雌性SD大鼠，使用浓度为40mg/kg的戊巴比妥钠通过腹腔注射麻醉大鼠。将大鼠固定于操作台，腿部剃毛后用碘伏消毒。在大鼠后腿的关节部位用手术刀割开5-8mm伤口，再用刀在股骨远端的松质骨部位割开肌肉组织，并用剥离子将松质骨部位的肌肉拨开露出骨头，用带有直径为0.8mm钻头的电钻在腿骨上预先钻一个小孔。最后，在36只大鼠中产生72个小孔缺损，并随机植入以下钛合金骨钉：(1)未进行修饰的钛合金骨钉(n＝24)；(2)细胞粘附多肽RGD修饰的钛合金骨钉(n＝24)；(3)实施例6制备的β-氨基酸聚合物修饰的钛合金骨钉(n＝24)。骨钉植入后，用可吸收的缝合线缝合伤口。手术后，允许动物自由获得鼠粮和水。分别在四周和八周两个时间点，通过腹腔注射过量的戊巴比妥钠处死大鼠。收集的每组样品一半用4％多聚甲醛溶液固定组织，另一半无需固定，直接用万能试验机将骨钉从骨组织中拉出，测试其生物力学性能。固定过的骨组织样品用Micro-CT定量分析每组植入材料的骨修复情况。
对于修饰的钛合金骨钉，先将钉子在UV/O3清洗机中清洗后修饰聚多巴胺涂层，之后将钉子浸没于RGD多肽或β-氨基酸聚合物溶液中反应过夜，获得RGD多肽或β-氨基酸聚合物修饰的钛合金骨钉。
结果显示：从Micro-CT的定量结果，组织学染色结果及生物力学结果都显示β-氨基酸聚合物修饰的钛合金骨钉实验组与未进行修饰的钛合金骨钉和RGD多肽修饰的钛合金骨钉的实验组相比，β-氨基酸聚合物修饰的钛合金骨钉实验组显著性的提高了植入体的骨整合效果。
实施例26：β-氨基酸聚合物修饰不锈钢植入体的体内骨整合活性测试
实验方法同实施例5，不同之处为将钛合金骨钉换为不锈钢骨钉。对于要修饰RGD多肽或β-氨基酸聚合物的不锈钢骨钉，先将钉子在UV/O3清洗机中清洗后修饰聚多巴胺涂层，之后将钉子浸没于RGD多肽或聚合物溶液中反应过夜，获得RGD多肽或聚合物修饰的不锈钢骨钉。
结果显示：从Micro-CT的定量结果显示β-氨基酸聚合物修饰的钛合金骨钉实验组与未进行修饰的钛合金骨钉和RGD多肽修饰的钛合金骨钉的实验组相比，β-氨基酸聚合物修饰的钛合金骨钉实验组显著性的提高了植入体的骨整合效果。
实施例27：β-氨基酸聚合物修饰白硅钙石植入体的大断骨修复活性测试
该实验采用大断骨缺损模型进行评价。实验动物为质量约180g-200g的八周雌性SD大鼠，使用浓度为40mg/kg的戊巴比妥钠通过腹腔注射麻醉大鼠。将大鼠固定于操作台，腿部剃毛后用碘伏消毒。在大鼠后腿的关节部位用手术刀割开5-8mm伤口，再用刀在大腿中部割开肌肉组织，并用剥离子将该部位的肌肉拨开露出骨头。然后用金属板上下固定股骨，使用线锯锯除股骨中段1cm的骨头。最后，在12只大鼠中产生个24个大断骨缺损，并随机植入以下材料：(1)未进行修饰的白硅钙石(n＝12)；(2)实施例6制备的β-氨基酸聚合物修饰的白硅钙石(n＝12)。材料植入后，用可吸收的缝合线缝合伤口。手术后，允许动物自由获得鼠粮和水。分别在四周和八周两个时间点，通过腹腔注射过量的戊巴比妥钠处死大鼠。收集样品并用4％多聚甲醛溶液固定组织。使用Micro-CT定量分析每组植入材料的骨修复情况。
对于修饰的白硅钙石支架，先在支架上修饰一层聚多巴胺涂层，之后将其浸没于β-氨基酸聚合物溶液中反应过夜，获得β-氨基酸聚合物修饰的白硅钙石支架。
结果显示：对于与未进行修饰的白硅钙石支架相比，β-氨基酸聚合物修饰的实验组大断骨修复效果显著性提高。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种氨基酸聚合物、或多肽模拟聚合物或其药学上可接受的盐的应用，其特征在于，用于修饰骨植入材料表面或掺杂于其内部；或者用于制备骨修复材料。
  2. 如权利要求1所述的应用，其特征在于，所述骨植入材料为不可降解的永久植入材料或可降解的植入材料。
  3. 如权利要求2所述的应用，其特征在于，所述不可降解的永久植入材料选自：钛、钛合金、钛镍合金、钽金属、镁金属、镁合金、不锈钢、钴铬合金、聚甲基丙烯酸甲酯、聚氨酯、聚醚醚酮、聚丙烯酰胺、聚乙烯醇。
  4. 如权利要求2所述的应用，其特征在于，所述可降解的植入材料选自：聚乳酸、聚(乳酸-羟基乙酸)共聚物、聚丙交酯、聚乙交酯、聚乙丙交酯、聚己内酯、聚已酸内酯、氧化铝、氧化锆、羟基磷灰石、磷酸三钙、生物玻璃、胶原、透明质酸、壳聚糖、海藻酸盐、丝素蛋白、纤维蛋白、明胶、纤维素。
  5. 如权利要求1所述的应用，其特征在于，所述骨修复材料的形式为水凝胶、电纺膜、3D打印支架、多孔支架、实心支架、骨水泥、可注射骨材料、体内交联骨材料、复合材料中的一种或两种以上的组合。
  6. 如权利要求1所述的应用，其特征在于，所述氨基酸聚合物或多肽模拟聚合物为选自下组的一种或两种以上的均聚物、二元共聚物或多元共聚物：α-氨基酸、β-氨基酸、γ-氨基酸、噁唑啉。
  7. 如权利要求6所述的应用，其特征在于，所述氨基酸聚合物或多肽模拟聚合物为噁唑啉聚合物、α-氨基酸聚合物、α/β-氨基酸聚合物、γ-氨基酸聚合物或β-氨基酸聚合物。
  8. 如权利要求6所述的应用，其特征在于，所述氨基酸聚合物或多肽模拟聚合物为以下Aa、Aa’、Bb、Bb’、Cc、Cc’、Cc”、Dd、Dd’、Ee、Ee’、Ff、Ff’和Gg结构组成的均聚物、二元共聚物或多元共聚物，重复单元总数为5-5000的正整数：
    Figure PCTCN2021131541-appb-100001
    Figure PCTCN2021131541-appb-100002
    其中，r在各出现处独立地为0、1、2、3、4或5；r'在各出现处独立地为1、2或3；r”在各出现处独立地为0、1、2或3；
    式中的R 1、R 2、R 3、R 4、R 5和R 6在出现处分别各自独立地选自以下基团：氢、C1-C6烷基、C1-C6卤代烷基、C1-C6烷基羟基、C1-C6烷氧基、C1-C6烷基磺酰基、C1-C6烷基胍基、C1-C6烷基酯基、硫代C1-C6烷基酯基、C2-C6烯基、C2-C6炔基、C3-C12环烷基、C6-C12芳基、5-12元杂芳基、5-12元杂环基、C1-C6烷基-C6-C12芳基、氨基和
    Figure PCTCN2021131541-appb-100003
    P 1为保护基，在各出现处独立地选自以下基团：叔丁氧羰基(Boc)、苄氧羰基(Cbz)、芴甲氧羰基(Fmoc)、邻苯二甲酰基(Pht)、乙酰基(Ac)、三氟乙酰基(Tfa)、苄基(Bn)、三苯基甲基(Tr)；
    P 2在各出现处独立地选自以下基团：氢、取代或未取代的C1-C6烷基、取代或未取代的C6-C12芳基、取代或未取代的5-12元杂芳基、取代或未取代的5-12元杂环基；
    X在各出现处独立地选自以下基团：无、氢、氨基、胍基、羟基、羧基、酰氨基、巯基、甲硫基、烯基、炔基、酯基、芳基或5-12元杂环基；
    L在各出现处独立地选自：-CHR' 1-、-CO-、-COO-、-S(＝O) 2-；q为0-6的整数；
    R' 1在各出现处独立地选自取代或未取代的以下基团：氢、氨基、C1-C15烷基、C1-C15烷基氨基、C1-C15烷基羟基、C1-C15烷基醛基、C1-C15烷基酯基、硫代C1-C15烷基酯基、C6-C15芳基、C2-C15烯基、C2-C15炔基、-Rc-COO-Rc”、-Rc-CO-Rc”、-Rc-O-Rc”-、-Rc-S-Rc”、5-15元杂芳基、5-12元杂环基；
    R a和R b在各出现处各自独立地选自取代或未取代的以下基团：不存在、氢、C1-C15烷基、C1-C15烷基氨基、C1-C15烷基羟基、C1-C15烷基醛基、C1-C15烷基磺酰基、C2-C15烯基、C2-C15炔基、-Rc-COO-Rc”、-Rc-CO-Rc”、-Rc-O-Rc”-、-Rc-S-Rc”、C3-C12环烷基、C4-C12环烯基、5-12元杂环基、C6-C12芳基、5-12元杂芳基；
    Rc在出现处分别各自独立地选自取代或未取代的以下基团：无、C1-C15亚烷基、C2-C15亚烯基、C2-C15亚炔基、C3-C12亚环烷基、C4-C12亚环烯基、3-12元亚杂环基、C6-C12亚芳基、5-12元亚杂芳基；
    Rc”在出现处分别各自独立地选自取代或未取代的以下基团：C1-C15烷基、C1- C15烷基氨基、C2-C15烯基、C2-C15炔基、C3-C12环烷基、C4-C12环烯基、3-12元杂环基、C6-C12芳基、5-12元杂芳基，
    上述各取代独立地指被选自以下一个或多个取代基取代：卤素、羟基、氨基、苯基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C3-C8环烷基。
  9. 如权利要求1所述的应用，其特征在于，所述氨基酸聚合物或多肽模拟聚合物选自：
    Figure PCTCN2021131541-appb-100004
    式中，n为5-5000的正整数；
    a为0-100的正整数；
    0％＜x≤100％,0％≤y≤100％，且x+y＝100％；
    R z选自：卤素、羧基、活性酯基团、酰氯、环氧烷、巯基、C2-C15烯烃基团、C2-C15炔基、叠氮、马来酰亚胺、邻二硫吡啶基(OPSS)、环糊精、金刚烷；
    R s在出现处分别各自独立地为氢或
    Figure PCTCN2021131541-appb-100005
    R t在各出现处各自独立地选自以下基团：C1-C15烷基、C1-C15烷基氨基、C2-C15烯基、C2-C15炔基、C3-C12环烷基、C4-C12环烯基、3-12元杂环基、C6-C12芳基、5-12元杂芳基；
    Rw为
    Figure PCTCN2021131541-appb-100006
    波浪线表示连接处；A’为0-12的正整数；式中的R 11、R 12、R 13和R 14在出现处分别各自独立地选自以下基团：氢、C1-C6烷基、C1-C6卤代烷基、C1-C6烷基羟基、C1-C6烷氧基、C1-C6烷基磺酰基、C1-C6烷基胍基、C1-C6烷基酯基、硫代C1-C6烷基酯基、C2-C6烯基、C2-C6炔基、C3-C12环烷基、C6-C12芳基、5-12元杂芳基、5-12元杂环基、C1-C6烷基-C6-C12芳基、氨基和
    Figure PCTCN2021131541-appb-100007
    P 1为保护基，在各出现处独立地选自以下基团：叔丁氧羰基(Boc)、苄氧羰基(Cbz)、芴甲氧羰基(Fmoc)、邻苯二甲酰基(Pht)、乙酰基(Ac)、三氟乙酰基(Tfa)、苄基(Bn)、三苯基甲基(Tr)；
    P 2在各出现处独立地选自以下基团：氢、取代或未取代的C1-C6烷基、取代或未取代的C6-C12芳基、取代或未取代的5-12元杂芳基、取代或未取代的5-12元杂环基；
    上述各取代独立地指被选自以下一个或多个取代基取代：卤素、羟基、氨基、苯基、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C3-C8环烷基。
  10. 如权利要求1所述的应用，其特征在于，所述氨基酸聚合物或多肽模拟聚合物选自：
    Figure PCTCN2021131541-appb-100008
    式中，n为5-5000的正整数；
    a为0-100的正整数；
    0％＜x≤100％,0％≤y≤100％，且x+y＝100％；
    R z选自：卤素、羧基、活性酯基团、酰氯、环氧烷、巯基、C2-C15烯烃基团、C2-C15炔基、叠氮、马来酰亚胺、邻二硫吡啶基(OPSS)、环糊精、金刚烷。
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